Skip to main content

Advertisement

SpringerLink
Log in

Preclinical studies of molecular-targeting diagnostic and therapeutic strategies against breast cancer

  • Conference Paper
  • Symposium: Molecular target therapy
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

We have investigated protein kinase C (PKC) signaling, a putative differentiation-related and metastasis suppressor gene Cap43/NDRG1/Drg-1, and Y-box binding protein-1 (YB-1) to identify new molecular targeting for breast cancer. PKC is a family of serine/threonine kinases that is involved in the regulation of cell growth. We have demonstrated that PKC caused G1 arrest in a breast cancer cell line through a mechanism involving a PKC–ERK MAPK–JNK–Rb protein signaling pathway. We have also characterized a novel mechanism through which all-trans retinoic acid (ATRA) and antineoplaston, anticancer drug, caused cell growth inhibition in breast cancer cells through effects on intracellular pathways. ATRA decreased the expression of PKCα, as well as reduced ERK MAPK phosphorylation, and consequently caused G1 arrest. Antineoplaston caused the down-regulation of PKCα protein expression, resulting in inhibition of ERK MAPK phosphorylation, with resultant inhibition of Rb phosphorylation leading to G1 arrest. PKC signaling represents a promising target for development of novel therapeutic agents. Cap43 is known as N-myc downstream-regulated gene 1 (NDRG1). Treatment with estradiol (E2) significantly decreased the expression of Cap43 in ER-α-positive breast cancer cell lines. Co-administration of tamoxifen abrogated the E2-induced downregulation of Cap43 in ER-α-positive cell lines. These results suggested that Cap43 may hold the potential of being a molecular marker to determine the therapeutic efficacy of anti-estrogenic anticancer agents in breast cancer. YB-1 is a member of the cold shock domain protein family. The expression of nuclear YB-1 was correlated with HER2 positively in clinical specimens of human breast cancer. Immunostaining studies showed that nuclear YB-1 expression was an independent prognostic factor of overall survival. Expression of nuclear YB-1 played an essential role in acquirement of malignant characteristics through HER2-dependent pathways in breast cancer patients. PKC, Cap43 and YB-1 may be useful in new molecular-targeting diagnosis and therapeutics in breast cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Abbreviations

PKC:

Protein kinase C

NDRG1:

N-myc downstream-regulated gene 1

Drg-1:

Differentiation-related gene-1

YB-1:

Y-box binding protein-1

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular signal-regulated kinase

JNK:

c-Jun NH2-terminal kinase

Rb:

Retinoblastoma

ATRA:

All-trans retinoic acid

E2 :

Estradiol

VEGF:

Vascular endothelial growth factor

EGFR:

Epidermal growth factor receptor

DAG:

Diacylglycerol

PMA:

Phorbol 12-myristate 13 acetate

References

  1. Baselga J, Albanell J, Ruiz A, Lluch A, Gascón P, Guillém V, González S, Sauleda S, Marimón I, Tabernero JM, Koehler MT, Rojo F. Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer. J Clin Oncol. 2005;23:5323–33.

    Article  PubMed  CAS  Google Scholar 

  2. Cobleigh MA, Langmuir VK, Sledge GW, Miller KD, Haney L, Novotny WF, Reimann JD, Vassel A. A phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol. 2003;30:117–24.

    Article  PubMed  CAS  Google Scholar 

  3. Canney PA, Machin MA, Curto J. A feasibility study of the efficacy and tolerability of the combination of Exemestane with the COX-2 inhibitor Celecoxib in post-menopausal patients with advanced breast cancer. Eur J Cancer. 2006;42:2751–6.

    Article  PubMed  CAS  Google Scholar 

  4. Musashi M, Ota S, Shiroshita N. The role of protein kinase C isoforms in cell proliferation and apoptosis. Int J Hematol. 2000;72:12–9.

    PubMed  CAS  Google Scholar 

  5. Newton AC. Protein kinase C: structure, function, and regulation. J Biol Chem. 1995;270:28495–8.

    Article  PubMed  CAS  Google Scholar 

  6. Schönwasser DC, Marais RM, Marshall CJ, Parker PJ. Activation of the mitogen-activated protein kinase/extracellular signal-regulated kinase pathway by conventional, novel, and atypical protein kinase C isotypes. Mol Cell Biol. 1998;18:790–8.

    PubMed  Google Scholar 

  7. Yokoyama G, Fujii T, Tayama K, Yamana H, Kuwano M, Shirouzu K. PKCδ and MAPK mediate G1 arrest induced by PMA in SKBR-3 breast cancer cells. Biochem Biophys Res Commun. 2005;327:720–6.

    Article  PubMed  CAS  Google Scholar 

  8. Donato LJ, Suh JH, Noy N. Suppression of mammary carcinoma cell growth by retinoic acid: the cell cycle control gene Btg2 is a direct target for retinoic acid receptor signaling. Cancer Res. 2007;67:609–15.

    Article  PubMed  CAS  Google Scholar 

  9. Veronesi U, Mariani L, Decensi A, Formelli F, Camerini T, Miceli R, Di Mauro MG, Costa A, Marubini E, Sporn MB, De Palo G. Fifteen-year results of a randomized phase III trial of fenretinide to prevent second breast cancer. Ann Oncol. 2006;17:1065–71.

    Article  PubMed  CAS  Google Scholar 

  10. Cho Y, Talmage DA. Protein kinase Cα expression confers retinoic acid sensitivity on MDA-MB-231 human breast cancer cells. Exp Cell Res. 2001;269:97–108.

    Article  PubMed  CAS  Google Scholar 

  11. Nakagawa S, Fujii T, Yokoyama G, Kazanietz MG, Yamana H, Shirouzu K. Cell growth inhibition by all-trans retinoic acid in SKBR-3 breast cancer cells: involvement of protein kinase Cα and extracellular signal-regulated kinase mitogen-activated protein kinase. Mol Carcinog. 2003;38:106–16.

    Article  PubMed  CAS  Google Scholar 

  12. Burzynski SR. The present state of antineoplaston research (1). Integr Cancer Ther. 2004;3:47–58.

    Article  PubMed  CAS  Google Scholar 

  13. Fujii T, Nakamura AM, Yokoyama G, Yamaguchi M, Tayama K, Miwa K, Toh U, Kawamura D, Shirouzu K, Yamana H, Kuwano M, Tsuda H. Antineoplaston induces G1 arrest by PKCα and MAPK pathway in SKBR-3 breast cancer cells. Oncol Rep. 2005;14:489–94.

    PubMed  CAS  Google Scholar 

  14. Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Takano Y, Saito K, Piquemal D, Commes T, Watabe M, Gross SC, Wang Y, Ran S, Watabe K. Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene. 2004;23:5675–81.

    Article  PubMed  CAS  Google Scholar 

  15. Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB. Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res. 2000;60:749–55.

    PubMed  CAS  Google Scholar 

  16. Bandyopadhyay S, Pai SK, Gross SC, Hirota S, Hosobe S, Miura K, Saito K, Commes T, Hayashi S, Watabe M, Watabe K. The Drg-1 gene suppresses tumor metastasis in prostate cancer. Cancer Res. 2003;63:1731–6.

    PubMed  CAS  Google Scholar 

  17. Fotovati A, Fujii T, Yamaguchi M, Kage M, Shirouzu K, Oie S, Basaki Y, Ono M, Yamana H, Kuwano M. 17β-estradiol induces down-regulation of Cap43/NDRG1/Drg-1, a putative differentiation-related and metastasis suppressor gene, in human breast cancer cells. Clin Cancer Res. 2006;12:3010–8.

    Article  PubMed  CAS  Google Scholar 

  18. Kuwano M, Oda Y, Izumi H, Yang SJ, Uchiumi T, Iwamoto Y, Toi M, Fujii T, Yamana H, Kinoshita H, Kamura T, Tsuneyoshi M, Yasumoto K, Kohno K. The role of nuclear Y-box binding protein 1 as a global marker in drug resistance. Mol Cancer Ther. 2004;3:1485–92.

    PubMed  CAS  Google Scholar 

  19. Janz M, Harbeck N, Dettmar P, Berger U, Schmidt A, Jürchott K, Schmitt M, Royer HD. Y-box factor YB-1 predicts drug resistance and patient outcome in breast cancer independent of clinically relevant tumor biologic factors HER2, uPA and PAI-1. Int J Cancer. 2002;97:278–82.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Yuji Basaki, Abbas Fotovati, Anna Nakamura, and Akihiko Kawahara for invaluable help in completing the studies presented in this article.

Author information

Authors and Affiliations

  1. Department of Surgery, Kurume University, Asahimachi 67, Fukuoka, 830-0011, Japan

    Teruhiko Fujii, Goro Yokoyama, Hiroki Takahashi, Shino Nakagawa, Uhi Toh & Kazuo Shirouzu

  2. Center for Innovative Cancer Therapy of the 21st Century COE Program for Medical Science, Kurume University, Fukuoka, Japan

    Teruhiko Fujii & Michihiko Kuwano

  3. Department of Surgery, Clinical Research Institute, National Hospital Organization Kyushu Medical Cancer, Fukuoka, Japan

    Teruhiko Fujii, Goro Yokoyama & Hiroki Takahashi

  4. Department of Radiology, Clinical Research Institute, National Hospital Organization Kyushu Medical Cancer, Fukuoka, Japan

    Roka Namoto

  5. Department of Pathology, Kurume University, Fukuoka, Japan

    Masayoshi Kage

Authors
  1. Teruhiko Fujii
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Goro Yokoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroki Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Roka Namoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Shino Nakagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Uhi Toh
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Masayoshi Kage
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazuo Shirouzu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michihiko Kuwano
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Teruhiko Fujii.

Additional information

This article is based on a presentation delivered at Symposium 3, “Molecular target therapy: basics and clinical application,” held on 30 June 2007 at the 15th Annual Meeting of the Japanese Breast Cancer Society in Yokohama.

About this article

Cite this article

Fujii, T., Yokoyama, G., Takahashi, H. et al. Preclinical studies of molecular-targeting diagnostic and therapeutic strategies against breast cancer. Breast Cancer 15, 73–78 (2008). https://doi.org/10.1007/s12282-007-0015-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-007-0015-y

Keywords

Search

Navigation